Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis
Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis
复制标题
辛伐他汀通过抑制 HIF-1 α/PPAR-γ/PKM2 介导的糖酵解使肝细胞癌细胞对索拉非尼重新敏感
DOI：
10.1186/s13046-020-1528-x
复制
发表时间：
2020-01-30
影响因子：
11.3
通讯作者：
Guo, Chuanyong
中科院分区：
文献类型：
--
作者：
Feng, Jiao;Dai, Weiqi;Guo, Chuanyong
背景肝细胞癌（HCC）是一种常见的原发性恶性肿瘤，由于诊断较晚，通常会进展至晚期。索拉非尼（Sora）是晚期 HCC 的一线药物；然而，它却面临着巨大的阻力。辛伐他汀 (Sim) 是一种降胆固醇药物，据报道可以抑制肿瘤生长。本研究旨在确定 Sora 和 Sim 联合治疗是否可以改善 HCC 中的 Sora 耐药性。方法利用肝癌细胞系LM3和已建立的Sora耐药LM3细胞系（LM3-SR）研究Sora耐药与有氧糖酵解之间的关系。通过蛋白质印迹、流式细胞术分析和生物医学测试来分析细胞增殖、凋亡和糖酵解水平。还使用异种移植模型来检查 Sim 的体内效果。还通过使用激活剂和抑制剂以及慢病毒转染进行了详细的机制研究。结果我们的结果表明，对 Sora 的抵抗力与有氧糖酵解水平的增强有关。此外，LM3-SR细胞比LM3细胞对Sim更敏感，这表明Sora和Sim联合处理可以增强LM3-SR细胞对Sora的敏感性。这一发现可能是由于 HIF-1 α/PPAR-gamma/PKM2 轴的抑制所致。结论 辛伐他汀可抑制HIF-1α/PPAR-γ/PKM2轴，通过抑制PKM2介导的糖酵解，导致HCC细胞增殖减少、细胞凋亡增加，并使HCC细胞对Sora重新敏感。
Background Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. Methods The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections. Results Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1 alpha/PPAR-gamma/PKM2 axis. Conclusions Simvastatin can inhibit the HIF-1 alpha/PPAR-gamma/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.